Intravaginal devices

ABSTRACT

The invention concerns an intravaginal device comprising a combination of 17 beta -estradiol and a supporting matrix for treating hypoestrogenic women. The device releases continously 17 beta -estradiol at a rate of about 0.5 to about 25  mu g/24 h. The invention also comprises a method of preparing the device and a method of treating hypoestrogenic women by using the device.

The present invention concerns intravaginal devices. Especially theinvention concerns intravaginal devices releasing a low amount of17β-estradiol for a prolonged period of time without undesirable sideeffects for treating hypoestrogenic women.

BACKGROUND

17β-estradiol is often used for treating estrogen deficiency. Thisdeficiency origins from e.g. oophorectomy, menopause, radiation-inducedovarian failure, panhypopituitarism and Kallman's syndrome.

When taken orally 17β-estradiol is relatively ineffective (1,2).Besides, oral estrogens effect the liver proteins due to portalabsorption (3), the intestinal metabolism (4,5) and "bolus" surges ofcirculating estrogen after each dose (5).

The problem with oral estrogen therapy can be avoided by vaginaladministration and steroids are well absorbed from vagina. Theadministration of 17β-estradiol via intravaginal devices has beensuggested and thoroughly studied (6,7,8,9). One of these studies, viz.the study by Englund et al (7), discloses intravaginal devices having anin vitro release rate of 200 μg/24 h, which corresponded to plasmalevels in the women varying between 80-200 pg/ml. In the end of thearticle it is concluded that the release rate of 200 μg per day is toohigh for replacement therapy in postmenopausal women as they exceed theestrogen levels seen in the follicular phase in fertile women. It issuggested that devices releasing 50-100 μg of 17β-estradiol per daymight deliver the proper dosage.

In the articles by Stumpf (6,9) and Veldhuls (8) the release rates perday are not discussed but the plasma levels disclosed are in the rangeof 50-150 pg/ml, which is about the same magnitude as disclosed in theEnglund article.

THE PRESENT INVENTION

Contrary to what has been studied and suggested it has now been foundthat intravaginal devices releasing a considerably lower amount of17β-estradiol is sufficient to alleviate or eliminate symptoms dependingon estrogen-deficiency. These symptoms may be e.g. feeling of vaginaldryness, pruritus, dyspareunia, smarting pain at micturition, urinaryurgency and frequency.

It has also been found that when the low dosage according to the presentinvention is used a drastical decrease of undesired side effects such asspotting, break-through and withdrawal bleeding is obtained.

The intravaginal devices according to the present invention arecharacterized in that they continuously release 17β-estradiol at a rateof about 0.5 to 25 μg/24 h.

The invention also concerns a method of treating hypoestrogenic women byretainably positioning within a woman a medicated intravaginal device,which continuously releases 17β-estradiol at a rate of about 0.5 toabout 25 μg/24 h.

Preferably the release rate varies between 1 and 10 μg/24 h, the mostsuitable release rate varying between 4 and 8 μg/24 h.

The period of continuous and essentially constant release of estradiolfrom the device according to the invention can include essentially anyperiod varying from a day to a year and this period will depend onseveral factors. A usual period is 3 or 4 months. Preferably the releaserate is essentially constant for at least a month.

The device according to the invention can have any shape adapted forintravaginal administration. A preferred type of device is theintravaginal ring.

In the field of intravaginal rings (IVR) there are basically fivedifferent designs. The first design concerns an IVR, wherein the steroidis homogenously dispersed throughout an inert elastomer as described inthe U.S. Pat. No. 3,545,397.

The second IVR consists of an inert elastomer ring encircled by a secondring of inert elastomer impregnated with a steroid (cf.e.g. the U.S.Pat. No. 4,012,496).

In a third type of IVR (the Roseman IVR) a thin layer of an inertelastomer containing a steroid is moulded onto a central inert core ofelastomer.

In the fourth type a thin medicated layer of an inert elastomercontaining a steroid surrounds a central inert core of syntheticelastomer and the medicated layer is surrounded by an outer layer ofinert elastomer of variable thickness. This type of ring is disclosed inthe U.S. Pat. No. 4,292,965.

A fifth type of IVR consists of a central core of elastomer that isadmixed with a steroid surrounded by an outer layer of inert elastomer.This type is described in CONTRACEPTION, Vol. 17, No. 3, pages 221-230,March 1978. The disclosures of these references are incorporated hereinby reference.

The invention also includes a method of preparing an intravaginal devicefor treating hypoestrogenic women. The method comprises the steps ofcombining 17β-estradiol and a supporting matrix, whereby the relativeamounts of 17β-estradiol and matrix are selected in such a way that thedevice will continuously release 17β-estradiol at a rate between about0.5 and 25 μg/24 h. Preferably the release rate varies from about 1 toabout 10 μg/24 h, and most preferably from about 4 to about 8 μg/24 h.

The elastomer of the matrix can be chosen from a wide variety ofmaterials known in the art and the release rate of the estradiol isgoverned by Fick's law. The elastomers can e.g. be chosen fromhydroxyl-terminated organopolysiloxanes of the RTV (room temperaturevulcanizing) type which harden to elastomers at room temperature afterthe addition of cross-linking agents in the presence of curing catalystsand under the atmospheric humidity. Typical curing catalysts aremetallic salts of carboxylic acids, preferably tin salts, e.g. tin (II)octoate and tin (II)-2-ethylhexanoate. Other suitable elastomers aretwo-component dimethylpolysiloxane compositions, which areplatinum-catalyzed at room temperature or under slightly elevatedtemperature and capable of addition cross-linking.

According to a preferred embodiment the device has the form of a ringthat may be prepared by homogenously suspending 17β-estradiol in apharmacologically acceptable elastomer; preparing a core from saidelastomer; mounting an outer layer of a pharmaceutically acceptableelastomer around the core and curing the device obtained.

It is obvious that the curing temperature and the curing time can varywithin broad ranges and depend i.a. on the elastomer used. The core andthe surrounding unmedicated layer can be made of the same elastomer.

The curing temperature may vary between room temperature and 150° C. andis preferably 40°-90° C. The curing time may vary between a few secondsto several days. In practice, however, curing times less than one hourare preferred.

In order to obtain the release rates according to the invention theratio between the core diameter and the thickness of the tubing shouldpreferably vary between 0.3 and 6, and most preferably between 0.4 and2.

EXAMPLES

The invention is further illustrated by the following examples:

EXAMPLE 1

One part of pure micronized 17β-estradiol was mixed with 250 parts offluid polydimethylsiloxane (382 Silastic® Medical Grade Elastomer). Themixture was activated by stannous octoate and injected under pressureinto two piece ring molds, each having an outside diameter of 543 mm andan inside diameter of 539 mm. The mixture in the molds was polymerizedand the solid rings having a crosssectional diameter of 2 mm were thenremoved. Silicone (382 Silastic® Medical Grade Elastomer)tubing having athickness of 3.5 mm was molded around the rings, thus resulting in afirst set of intravaginal rings consisting of a medicated inner 2 mmcore and an unmedicated outer 3.5 mm layer. These rings releasedapproximately 8 μg/24 h of estradiol for a period of 150 days. Thecontent of estradiol was 1.91 mg/ring and of Silastic® 11 g.

EXAMPLE 2

A second set of intravaginal rings was similarly produced and releasedapproximately 20 μg/24 h of estradiol for a period of 150 days, thedifference in such rings being that an unmedicated outer, 1.5 mm thicklayer of silicone tubing and a core having a diameter of 6 mm were used.The release rate during the 150 days period of time was fairly constant,but the rate does tend to decrease slightly with time. The content ofestradiol was 4.79 mg/ring and of Silastic® 11 g.

The release rates referred to herein are in vitro release rates, whichmay be measured according to the procedure set on page 225 of the March1978 issue of CONTRACEPTION (Vol. 17, No. 3) or the October 1981 issueof CONTRACEPTION (Vol. 24, No. 4) or by any other comparable method.

Thus, one may produce intravaginal devices containing 17β-estradiol inany of a number of different ways, having any of a number of differentforms or shapes. The above release rate testing procedure can be used todetermine whether such devices meet the release rate requirements ofthis invention.

Whereas the foregoing examples involve an admixture of 17β-estradiol andan elastomer, we also contemplate that the 17β-estradiol could be in acarrier liquid, emulsion, gel or oil within a surrounding elastomericshell that is porous enough to permit controlled release of the17β-estradiol.

The rings releasing about 8 μg/24 h were tested on 9 postmenopausalwomen and the rings releasing about 20 μg/24 h were tested on 11post-menopausal women for a period of three months. The rings were wellaccepted and the post-menopausal symptoms disappeared in both groups.

No side effects were observed in the women obtaining the estradiol atthe rate of 8 μg/24 h. A negligible bleeding was observed in one womanreceiving the dose 20 μg/24 h.

Table 1 discloses the in vitro release rate of 17β-estradiol from thetwo types of rings prepared according to the Examiner.

The tables 2 and 3 indicate the in vivo release rates as well as thecorrelation between in vitro and in vivo release rate.

                  TABLE                                                           ______________________________________                                        Release of E.sub.2 from IVR in vitro (0.9% saline).                           Mean values of 3 rings.                                                       Time,        Released E.sub.2, ug/24 h                                        days         A         B                                                      ______________________________________                                        5            24        9                                                      10           23        9                                                      15           23        9                                                      20           22        9                                                      25           21        8                                                      30           21        8                                                      35           20        8                                                      40           20        8                                                      45           20        8                                                      50           20        8                                                      60           19        7                                                      70           18        7                                                      80           18        7                                                      90           17        7                                                      100          16        7                                                      110          15        7                                                      120          14        7                                                      140          14        7                                                      ______________________________________                                         A = rings containing 4.79 mg estradiol                                        B = rings containing 1.91 mg estradiol                                   

                                      TABLE 2                                     __________________________________________________________________________    Release of E.sub.2 in vivo. Analyses of rings type A after use.               Content of E.sub.2 before clinical trial: 4.79 mg/ring                        (mean value of 13 analyzed rings)                                             Analyses after clinical trial:                                                Patient                                                                            a  b  c  d  e  f  g  h  i  j  k  Mean                                    __________________________________________________________________________    Time of                                                                       usage,                                                                             98 97 97 97 98 98 92 98 98 98 105                                        days                                                                          Content                                                                       of E.sub.2                                                                         2.66                                                                             3.00                                                                             3.29                                                                             2.86                                                                             2.66                                                                             2.51                                                                             2.87                                                                             2.86                                                                             2.80                                                                             2.74                                                                             2.71                                       after use,                                                                    mg                                                                            E.sub.2 re-                                                                   leased,                                                                            2.13                                                                             1.79                                                                             1.50                                                                             1.93                                                                             2.13                                                                             2.28                                                                             1.92                                                                             1.93                                                                             1.99                                                                             2.05                                                                             2.08                                       mg                                                                            Mean                                                                          dosage,                                                                            21.7                                                                             18.5                                                                             15.5                                                                             19.9                                                                             21.7                                                                             23.3                                                                             20.9                                                                             19.7                                                                             20.3                                                                             20.9                                                                             19.8                                                                             20.2                                    μg/day                                                                     Ratio                                                                         in vivo/                                                                           1.07                                                                             0.91                                                                             0.76                                                                             0.98                                                                             1.07                                                                             1.15                                                                             1.01                                                                             0.97                                                                             1.00                                                                             1.03                                                                             1.04                                                                             1.00                                    in vitro                                                                      __________________________________________________________________________

                                      TABLE 3                                     __________________________________________________________________________    Release of E.sub.2 in vivo. Analyses of rings type B after use.               Content of E.sub.2 before clinical trial: 1.91 mg/ring                        (mean value of 10 analyzed rings /1.84-2.00/)                                 Patient                                                                              1  m  n  o  p  q  r  s  t  Mean                                        __________________________________________________________________________    Time of                                                                       usage, days                                                                          98 98 98 98 98 93 99 98 98                                             Content of E.sub.2                                                            after use                                                                            1.18                                                                             1.21                                                                             1.35                                                                             1.17                                                                             1.31                                                                             1.41                                                                             1.13                                                                             1.32                                                                             1.18                                           E.sub.2 released,                                                             mg     0.73                                                                             0.70                                                                             0.56                                                                             0.74                                                                             0.60                                                                             0.50                                                                             0.78                                                                             0.59                                                                             0.73                                           Mean dosage,                                                                  ug/day 7.4                                                                              7.1                                                                              5.7                                                                              7.6                                                                              6.1                                                                              5.4                                                                              7.9                                                                              6.0                                                                              7.4                                                                              6.6                                         Ratio in vivo                                                                 /in vitro                                                                            0.95                                                                             0.91                                                                             0.73                                                                             0.97                                                                             0.78                                                                             0.69                                                                             1.01                                                                             0.77                                                                             0.95                                                                             0.84                                        __________________________________________________________________________

REFERENCES

1. Botella-Llusia J 1973 Endocrinology of Women, W. B. Saunders Co,Philadelphia, pp 32-33

2. Krantz J. C., Carr C. J., LaDu BN 1969 The Pharmacologic Principlesof Medical Practice. Williams & Wilkins Co, Baltimore, p 597

3. Utian W.H. 1980 Menopause in Modern Perspective: A Guide to ClinicalPractice, Appleton-Century-Crofts, New York, pp 151-152

4. Ryan K. J., Engel L. L. 1953 The Interconversion of estrone andestradiol by human tissue slices. Endocrinol. 52:287

5. Yen S. S. C., Martin P. L., Burnier A. M., Czekala N. M., Greaney M.O., Callantine M. R. 1975 Circulating estradiol, estrone andgonadotropin levels following the administration of orally active17β-estradiol in postmenopausal women, J Clin Endocrinol Metab 40:518

6. Stumpf et al 1982, Development of a vaginal ring for achievingphysiologic levels of 17β-estradiol in hypoestrogenic women, J ClinEndocrinol Metab, 54:208-210

7. Englund D. E., 1981, Pharmacokinetics and pharmacodynamic effects ofvaginal oestradiol administration from silastic rings in postmenopausalwomen, Maturitas, 3:125-133

8. Veldhuls J. et al, 1986, Endocrine impact of pure estradiolreplacement in postmenopausal women: Alterations in anterior pituitaryhormone release and circulating sex steroid hormone con

9. Stumpf. P. 1986, Selecting constant serum estraestradiol levelsachieved by vaginal rings, Obstet. Gynecol. 67:91-94, 1986

We claim:
 1. An intravaginal device for use by hoypoestrogenic women inthe form of a ring which consists of a core of a pharmacologicallyacceptable elastomer and an outer elastomer layer surrounding said core,said core having 17 beta-estradiol homogeneously suspended therein insuch a way that the 17 beta-estradiol will be continuously released fromthe ring at an essentially constant rate of about 0.5 to 25 μg per 24hours for at least a month.
 2. An intravaginal device according to claim1 wherein the release rate is from about 1 to about 10 μg/24 h.
 3. Anintravaginal device according to claim 1 wherein the release rate isfrom about 4 to about 8 μg/24 h.
 4. An intravaginal device according toclaim 1 wherein said core elastomer is a polydimethylsiloxane and saidouter elastomer layer is silicone tubing.
 5. A method of treating awoman having symptoms of hypoestrogenicity which comprises positioningwithin the woman an intravaginal device in the form of a ring whichconsists of a core of a pharmacologically acceptable elastomer and anouter elastomer layer surrounding said core, said core having 17beta-estradiol homogeneously suspended therein in such a way that the 17beta-estradiol will be continuously released from the ring at anessentially constant rate of about 0.5 to 25 μg per 24 hours for atleast a month.
 6. A method according to claim 5 wherein the release rateis from about 1 to about 10 μg/24 h.
 7. A method according to claim 5wherein the release rate is from about 4 to about 8 μg/24 h.
 8. A methodaccording to claim 5 wherein said core elastomer is apolydimethylsiloxane and said outer elastomer layer is silicone tubing.